2. Academic Validation
  3. A PROTAC degrader suppresses oncogenic functions of PTK6, inducing apoptosis of breast cancer cells

A PROTAC degrader suppresses oncogenic functions of PTK6, inducing apoptosis of breast cancer cells

  • Cell Chem Biol. 2025 Feb 20;32(2):255-266.e8. doi: 10.1016/j.chembiol.2024.10.008.
Criseyda Martinez 1,  Yan Xiong 2,  Alison Bartkowski 1,  Ibuki Harada 1,  Xiaoxiao Ren 2,  Jessica Byerly 1,  Elisa Port 3,  Jian Jin 4,  Hanna Irie 5
Affiliations

Affiliations

  • 1 Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 2 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3 Department of Surgery, Mount Sinai Hospital, New York, NY 10029, USA.
  • 4 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: jian.jin@mssm.edu.
  • 5 Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: hanna.irie@mssm.edu.
PMID: 39541980 DOI: 10.1016/j.chembiol.2024.10.008
Abstract

Protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase, is an oncogenic driver in many tumor types. However, agents that therapeutically target PTK6 are lacking. Although several PTK6 kinase inhibitors have been developed, none have been clinically translated, which may be due to kinase-independent functions that compromise their efficacy. PTK6 kinase inhibitor treatment phenocopies some, but not all effects of PTK6 downregulation. PTK6 downregulation inhibits growth of breast Cancer cells, but treatment with PTK6 kinase inhibitor does not. To chemically downregulate PTK6, we designed a PROTAC, MS105, which potently and specifically degrades PTK6. Treatment with MS105, but not PTK6 kinase inhibitor, inhibits growth and induces Apoptosis of breast Cancer cells, phenocopying the effects of PTK6 (short hairpin RNA) shRNA/CRISPR. In contrast, both MS105 and PTK6 kinase inhibitor effectively inhibit breast Cancer cell migration, supporting the differing kinase dependencies of PTK6's oncogenic functions. Our studies support PTK6 degraders as a preferred approach to targeting PTK6 in Cancer.

Keywords

BRK; PROTAC; PTK6; apoptosis; breast cancer; degraders.

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